REVIEW

CURRENT
OPINION The diagnostic utility of autoantibodies in adult and
juvenile myositis
Sarah L. Tansley a, Zoe E. Betteridge b, and Neil J. McHugh a

Purpose of review
The purpose of this study is to review recent advances in the diagnostic utility of autoantibodies in
dermatomyositis.
Recent findings
Alternative nonspecialist testing methods have been developed for anti-transcription intermediary factor 1
gamma, anti-MDA5 and anti-nuclear matrix protein 2, which are potentially exploitable by any hospital
laboratory. Although these have yet to be validated for diagnostic use, it is likely that testing for myositis-
specific antibodies will soon become readily available.
Summary
The identification of myositis-specific autoantibodies provides both diagnostic and prognostic information
and offers a unique opportunity to adopt a stratified approach to treatment. Their identification, in many
cases, should prevent the need for invasive diagnostic tests such as muscle biopsy.
Keywords
autoantibody, diagnosis, myositis, prognosis

INTRODUCTION in addition to the presence of myositis-specific or

Both adult and juvenile-onset dermatomyositis are
characterized by proximal muscle weakness and
a pathognomic rash consisting of heliotrope dis-
colouration around the eyes, Gottron’s papules, a
violaceous rash on the elbows and knees, the v-sign
and shawl sign. Despite this, the diagnosis may not
always be straightforward: Amyopathic myositis con-
sists of the characteristic dermatomyositis rash in the
absence of any evidence of muscle inflammation or
weakness [1]. This type of presentation is more com-
mon in East Asian populations wherein it is associ-
ated with interstitial lung disease (ILD) and a poor
&
prognosis [2 ,3]. Alternatively, the rash can be subtle
and easily missed and in juvenile dermatomyositis
(JDM) particularly can be atypical, occurring any-
where on the body. The rarity of dermatomyositis
combined with potentially subtle clinical findings
can lead to diagnostic delay. This is potentially dis-
astrous in juvenile-onset disease in which delay in
diagnosis and the initiation of treatment are associ-
ated with a worse clinical outcome and an increased
risk of calcinosis, a major cause of morbidity [4,5].
The diagnostic criteria for dermatomyositis at
present remain those described by Bohan and Peter
in 1975. These are now outdated and do not
include modern imaging techniques, such as MRI,
associated antibodies. Attempts are currently under-
way by expert groups to revise these criteria. Accord-
ing to the currently used Bohan and Peter diagnostic
criteria, a muscle biopsy is generally, although not
always, required to make the diagnosis. This test is
invasive, particularly when performed in children,
in whom a general anaesthetic is typically required.
Many centres now choose not to routinely perform
muscle biopsies reaching the diagnosis on clinical
grounds with the help of basic blood tests, autoanti-
body testing where available, MRI scans and in
adults an electromyography. Where muscle biopsy
is performed, findings can be subtle or nonspecific,
particularly if treatment such as steroids has been
previously started. This again may lead to a diag-
nostic delay or uncertainty in nonspecialist centres,
particularly in the absence of a classic dermatomyo-
sitis skin rash.
a
Royal National Hospital for Rheumatic Diseases and bUniversity of Bath,
Bath, UK
Correspondence to Neil J. McHugh, Royal National Hospital for Rheu-
matic Diseases, Upper Borough Walls, Bath BA1 1RL, UK. Tel: +1225
463223; fax: +1225 473437; e-mail: Neil.McHugh@rnhrd.nhs.uk
Curr Opin Rheumatol 2013, 25:772–777
DOI:10.1097/01.bor.0000434664.37880.ac

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KEY POINTS

Widely available testing for autoantibodies found in
myositis is likely to become possible in the short-
medium term.

A negative anti nuclear antibody or the detection of less
specific autoantibodies should not deter further
investigation for the presence of myositis-specific
autoantibodies.

Autoantibodies in myositis can both facilitate diagnosis
and inform on prognosis.

The titre of some autoantibodies may be clinically useful
as disease activity markers.

Patient responsiveness to treatments such as B-cell
depletion may vary depending on serological profile.
In addition to the lack of an acceptable diagnostic
test, both juvenile and adult-onset dermatomyositis
are heterogeneous conditions, and at present, there
are no validated tests that facilitate the targeting of
those at risk of severe disease, prior to the develop-
ment of complications such as calcinosis, ulceration
or ILD nor the early identification of adults with an
associated malignancy. Here, we discuss the utility of
myositis-specific autoantibodies (MSAs) in disease
diagnosis and adopting a stratified approach to fur-
ther investigation and management.
MYOSITIS-SPECIFIC AUTOANTIBODIES
Autoantibodies directed against intracellular anti-
gens are frequently found in connective tissue dis-
eases. Although their mechanistic relevance to
disease pathogenesis is not fully understood, they
are clinically useful, often specific and constitute
part of the diagnostic criteria for many diseases.
Myositis-specific or associated antibodies are detect-
able in the majority of children and adults with
dermatomyositis: approximately 60% with juven-
ile-onset and 80% with adult-onset disease (personal
data). Although dermatomyositis is a heterogeneous
disease, MSA can divide patients into homogenous
subgroups and inform on prognosis. The pheno-
typic associations of MSA and recent advances in
our understanding have recently been reviewed in
&& &&
[6 ] and are summarized in Table 1 [7–10,11 ].
Although specific, the phenotypic associations of
MSA have been seen to differ depending on whether
&
they are found in adult or juvenile-onset disease [12 ].
These differences can be significant as, for example,
in adults, the presence of anti-transcription interme-
diary factor 1 gamma (TIF1g) is highly suggestive of
an associated cancer, whereas in children this MSA is
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Diagnostic utility of autoantibodies Tansley et al.
commonly seen and associated with skin ulceration
and oedema but is not linked to malignancy [8,13].
Phenotypic variation with MSA subgroups has also
been seen between populations, for example in East
Asian populations, anti-MDA5 is associated with
amyopathic myositis, rapidly progressive ILD and a
poor prognosis; however, in predominantly white
populations, a characteristic cutaneous phenotype
is described, and although ILD is also associated in
whites, it tends not to be rapidly progressive and
responds well to standard treatment [2 ,13–15].
&
The overall prognosis is therefore likely to be further
influenced by additional factors including age,
genetics and the environment.
MSA are highly specific for dermatomyositis and
are useful in establishing diagnosis as well as prog-
&&
nosis [6 ]. MSA are typically mutually exclusive but
&
have occasionally been reported to coexist [16,17 ].
They have also been identified in conjunction with
less specific autoantibodies; for example, the combi-
nation of anti-MDA5 with anti-Ro52 was reported to
be a common finding in two studies [14,15]. Anti-
Ro60 and Ro52 have also been identified in a high
proportion of patients with anti-PL-7 [18]. The detec-
tion of less specific autoantibodies should not there-
fore deter further investigation for the presence
of MSA.
ANTIGENIC TARGETS OF MYOSITIS-
SPECIFIC AUTOANTIBODIES
Although their mechanistic relevance to disease
pathogenesis is not fully understood, MSAs fre-
quently target nuclear or cytoplasmic cellular com-
ponents that are involved in gene transcription,
protein translocation and antiviral responses. Inter-
estingly, the antigenic targets of MSA that have been
linked to the development of malignancy in adults
have important roles to play in cell growth and DNA
repair. For example, TIF1g is a nuclear factor that via
SMAD4 plays an important role in transforming
growth factor beta (TGFb) signalling and suppres-
sion of cell growth [19] and nuclear matrix protein 2
(NXP2) regulates the activation and subcellular
localization of tumour suppressor gene p53 [20].
Interestingly, autoantigens with comparable
cellular functions such as the tRNA-synthetases
are associated with similar disease phenotypes [7].
The antisynthetase syndrome is characterized by
myositis, ILD, fever, Raynaud’s phenomenon,
arthritis and mechanics hands [21]. Although all
antisynthetase antibodies described can share these
clinical features, differences, including the preva-
lence of pulmonary manifestations, have been
described depending on the specific antibody.
Patients with anti-Jo1, anti-PL-7 or anti-EJ typically
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 Myositis and myopathies

Table 1. The phenotype of myositis-specific autoantibody subgroups and important associated complications
Dermatomyositis-associated autoantibodies

Phenotype Important complications Frequency (% IIM)

a
Antisynthetases [7] Myositis, ILD, fever, Raynaud’s phenomenon, arthritis and ILD Juvenile: 1–3%;
mechanics hands. Can present as ILD alone Adult: 30–40%
&&
Anti-Mi2 [6 ,7] Classic DM skin lesions, mild disease Juvenile <10%;
Adult <10%
&&
Anti-MDA5 [6 ] East Asian populations: amyopathic DM, rapidly ILD; Ulceration Juvenile 7%
progressive ILD, poor prognosis; US populations: mild (personal data);
muscle disease, mucocutaneous ulceration, tender Adult 13–35%
palmar papules, arthritis, ILD
&&
Anti-TIF1g [6 ,7,8] Juvenile disease: cutaneous ulceration and oedema; Adult Juvenile disease: Ulceration; Juvenile 23–29%;
disease: severe cutaneous disease Malignancy Adult disease: Malignancy Adult 13–21%
&&
Anti-NXP2 [6 ] Juvenile disease: calcinosis, severe disease course, Juvenile disease: Calcinosis; Juvenile 23–25%;
persistent disease activity and worse functional status; Adult disease: Possibly Adult 1.6–17%
Adult disease: possible associations with malignancy calcinosis and malignancy
and calcinosis described
Anti-SAE [7] Adult disease: initially amyopathic disease Adults: dysphagia Juvenile <1%;
Adults 5%
Necrotizing myositis-associated autoantibodies
Phenotype Important complications Frequency (% IIM)

&&
Anti-SRP [6 ,7] Severe disease with rapid onset. Less frequent cutaneous Severe myopathy, dysphagia; Adult 5%
disease, ILD, Raynauds, arthritis and overlap with other possibly cardiac involvement
connective tissue diseases
&&
Anti-HMGCR [6 ] Prior statin exposure Adult 6%
Inclusion body myositis-associated autoantibodies
&&
Anti-Mup44 [9,10,11 ] Inclusion body myositis Important complications Frequency (% IIM)
33% IBM, 4%
DM/PM

a
Anti-Jo1, Anti-PL-7, Anti-PL-12,Anti EJ, Anti-OJ, Anti-KS, Anti-Ha, Anti-Zo. DM, dermatomyositis; HMGCR, HMG-co-A reductase; IBM, inclusion body myositis; IIM,
idiopathic inflammatory myopathy; ILD, interstitial lung disease; MDA5, melanoma associated differentiation gene 5; NXP2, Nuclear Matrix Protein 2; PM,
polymyositis; SAE, small ubiquitin like modifier activating enzyme; SRP, signal recognition peptide.

have obvious muscular symptoms, whereas, in con-
trast, patients with anti-PL-12, anti-KS or anti-OJ
often have predominant ILD [7]. This was supported
in a recent Japanese study of 166 patients with anti-
synthetase antibodies, in which 29% anti-Jo-1, 16%
anti-EJ, 10% anti-PL-7 and 11% anti-PL-12 presented
initially with ILD alone, and although many sub-
sequently developed myositis and other disease fea-
tures, this was less likely in those with anti-PL-12,
anti-KS and anti-OJ. In contrast, of patients with
myositis alone at presentation, nearly all sub-
&
sequently developed ILD during the follow-up [17 ].
A subgroup of patients with antisynthetase anti-
bodies are therefore likely to, at least initially, present
with respiratory symptoms in the absence of other
myositis features. A retrospective study [22] of 198
cases with idiopathic interstitial pneumonias was
able to demonstrate the presence of antisynthetase
antibodies in 6.6% of cases (3% anti-EJ, 1.5% anti-PL-
12 and 0.5% each anti-Jo-1, anti-KS, anti-OJ and anti-
PL-7). This group had a younger median age of onset
in addition to more arthralgia and cutaneous mani-
festations; however, extra-pulmonary features of the
antisynthetase syndrome were absent in 46.2% of
cases. Although most patients had a nonspecific
interstitial pneumonia pattern typically seen in con-
nective tissue disease associated ILD, two cases had
usual interstitial pneumonia on biopsy [22].
Perhaps due to differing presentation and avail-
ability of antibody testing, patients with antisynthe-
tase antibodies other than anti-Jo-1 have been shown
to have a greater delay in diagnosis than those with
&&
anti-Jo-1 and also reduced survival [23 ]. The most
common cause of death in those with antisynthetase
antibodies is ILD and the 10-year adjusted cumulative
&&
survival is just 47% for non-Jo-1 patients [23 ].
MSA testing in these situations can potentially
identify a unifying diagnosis from the outset, prior
to the onset of any myopathy and without further
invasive tests such as lung biopsy. It may enable the
earlier initiation of immunosuppressive treatment
and result in stabilization of lung disease. This is
particularly relevant for those few patients with a
usual interstitial pneumonia pattern in whom, in
the absence of associated connective tissue disease,
treatment options are limited.

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Developments have also been made in the pres-
ence of specific autoantibodies in patients with
inclusion body myositis (IBM). Autoantibodies to
a 44-kDa protein (termed Mup44) and a 43-kDa
target were concurrently described by Pluk et al.
[9] and Slajegheh et al. [10]. Mup44 was identified
by western blotting using a skeletal muscle cell
extract and was found in 27% of sporadic IBM
patients tested, in comparison to 0% dermatomyo-
sitis and 2% polymyositis. Similarly, the anti-43 kDa
autoantibodies were detected using immunoblots
on human muscle lysates and were found in 52%
of IBM patients and no other autoimmune myo-
pathic or healthy controls [9,10]. Blotting and
immunoprecipitation studies using alternative cell
lines and sources have been unable to detect this
autoantigen, demonstrating the need for disease-
specific protein sources for some autoantibodies
&&
[11 ].
More recently, the target autoantigen for both
the 43-kDa and Mup44 studies has been identified as
cytosolic 50 -Nucleotidase 1A [11 ,24 ]. Further
&& &&
studies have shown that this autoantibody has a
high sensitivity for IBM (31–70%), with a specificity
of 91–97%. Interestingly, although anti-Mup44 was
found at low levels in a small number of polymyositis,
dermatomyositis and neuromuscular controls, it was
&&
not seen in normal healthy controls [11 ,24 ].
Of interest, no difference in age, duration of symp-
toms, weakness, anti nuclear antibody positivity or
anti-Ro/La positivity has been seen in Mup44-
&&
positive versus negative IBM patients [24 ]. More
studies are therefore required to determine whether
the presence of this autoantibody distinguishes a
subset of IBM patients.
IDENTIFICATION OF MYOSITIS-SPECIFIC
AUTOANTIBODIES
Standard immunology screening tests such as
immunofluorescence generally provide very little
information in myositis. At present, a standard hos-
pital laboratory ‘autoimmune screen’ is unlikely to
detect MSA other than anti-Jo-1. A ‘negative’ result
should not therefore deter further investigation
where myositis or connective tissue disease associ-
ated ILD is suspected. Although commercially avail-
able testing is available for many MSA including the
most common antisynthetases, anti-signal recog-
nition peptide (SRP) and recently anti-MDA5, the
lack of perceived availability of testing for MSA
limits their current diagnostic utility. This is particu-
larly relevant in JDM where the two most common
MSA, anti-TIF1g and anti-NXP2, which together
account for nearly 50% of all patients, do not
have commercial testing kits available. At present,
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Diagnostic utility of autoantibodies Tansley et al.
worldwide, only a handful of laboratories offer an
accredited diagnostic service for all MSA and use
the specialist technique of immunoprecipitation.
Immunoprecipitation is generally viewed as expen-
sive, and although this method is the current ‘gold-
standard’, it is low-throughput and interpretation of
results is subjective. With growing evidence of the
utility of MSA both diagnostically and prognosti-
cally, there is an increasing interest in developing
alternative techniques that could be used in the
routine hospital laboratory setting. ELISAs have
been developed by many research groups who are
able to detect anti-TIF1g, anti-NXP2, anti-MDA5
and anti-HMG-co-A reductase (HMGCR), but these
have yet to be validated for diagnostic use
&& &
[3,25 ,26 ,27]. ELISA testing is commercially avail-
able for detection of most antisynthetases. In
addition to ELISA, other testing methods investi-
gated have included immune-blot, line-immunoas-
say and addressable laser bead immunoassays
[13,28]. Line-immunoassay has the advantages of
being easy to use and allows testing for multiple
autoantibodies simultaneously but is only semi-
quantitative and the sensitivity for some autoanti-
bodies is lower than with other methods [29].
Although sensitivity can sometimes be reduced,
we have found that this method is generally specific
&&
and produces reliable results. There is a strong inter-
est in developing more comprehensive assays for
diagnostic use, and with new commercial kits for
MSA screening becoming available, it seems likely
that routine testing for MSA will be available in the
near future.
MYOSITIS-SPECIFIC AUTOANTIBODY
TITRE
The development of quantitative techniques for
MSA detection has generated an interest in potential
implications of MSA titre. Autoantibody titre has
already proved to be useful in other rheumatological
diseases for monitoring disease activity and predict-
ing relapse, such as with anti-dsDNA antibodies in
lupus. The best studied MSA in this regard is anti-
MDA5: in adults, the titre of anti-MDA5 has been
shown to correlate with the risk of developing
rapidly progressive ILD and subsequent mortality
&
[2 ]. Furthermore, anti-MDA5 antibodies have been
shown to disappear during disease remission [30].
The implications of anti-MDA5 titre in juvenile
disease are not yet fully understood, but anecdotally
a higher titre of anti-MDA5 was noted in children
who developed rapidly progressive ILD [31], and the
utility of anti-MDA5 titre in predicting treatment
response has also been reported in small studies [32].
Similarly to other studies looking at anti-MDA5
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 Myositis and myopathies
phenotype, current literature reports looking at the
impact of titre are primarily clustered on East Asian
populations, particularly Japan. Given the apparent
differences in clinical phenotype, including the risk
of rapidly progressive ILD, seen as dependent on the
ethnic background of the population studied, the
results may not be applicable in all populations. A
single US-based study has analysed anti-MDA5 titre
in a predominantly white population; however,
only six patients with anti-MDA5 were studied lon-
gitudinally and different methodology was used
making results difficult to compare with other
studies. Although in general less severe disease
was seen in patients with lower titres of anti-
MDA5, titre did not vary much over the follow-up
period or correlate with disease course [15].
Other MSA have also been examined from a titre
perspective with interesting results: anti-Jo-1 levels
have been shown to correlate with disease activity in
adults [33], and recently, a reduction in anti-Jo-1
titre was described in response to B cell depletion
with rituximab. Furthermore, this reduction in titre
correlated with improvement in core disease activity
measures [34]. Similarly, anti-SRP and anti-HMGCR
levels have also been associated with disease activity
&
and creatinine kinase level [28,35 ]. The initial titre
of anti-TIF1g in adults has been demonstrated to
correlate with the likelihood of malignancy, with
higher titres showing a greater specificity for associ-
ated malignant disease [36]. Although the studies
described are generally small and further work is
needed, preliminary results are encouraging and
highlight further potential utility for MSA in pre-
dicting prognosis and disease monitoring.
IMPLICATIONS OF MYOSITIS-SPECIFIC
AUTOANTIBODIES FOR DISEASE
MANAGEMENT AND TREATMENT
APPROACH
MSAs are identifiable at disease onset by simple blood
test in the majority of adults and children with
dermatomyositis. They provide a means to confirm
the diagnosis without the need for further invasive
tests in many cases. Not only does this offer the
opportunity for more rapid diagnosis and initiation
of treatment but also for a stratified approach to
further investigation and management. MSA divide
patients into relatively homogenous subgroups with
defined associated complications and could be used
to guide the need for investigations such as HRCT in
those at risk of ILD or further imaging with PET
computed tomography (CT) in adults at a high risk
of associated malignancy. Where calcinosis is a high
risk in JDM, this could also potentially influence
treatment decisions.
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In patients with IBM although reaching the
diagnosis earlier is unlikely to result in the avail-
ability of specific treatments, it will provide import-
ant prognostic information. A study [37] on 107
patients demonstrated a biopsy to have an 85%
diagnostic accuracy in the diagnosis of IBM. This
is similar to that reported for anti-Mup44 testing
&&
[24 ]. The diagnosis of IBM can be particularly
difficult and in the absence of a characteristic biopsy
may take several years. The development of a test for
autoantibodies in IBM may therefore decrease the
reported median delay to IBM diagnosis (currently
of 4.9–5.2 years) and the current mis-diagnosis rate
&&
(30–54%) [24 ,28,38].
To date, treatment regimens in dermatomyositis
are based on clinical experience and expert opinion
rather than evidence-based guidelines. There is a
general lack of good quality randomized controlled
trials (RCTs) assessing the efficacy and toxicity of
different therapeutic options and several studies
have demonstrated negative results [39]. The hetero-
geneity of dermatomyositis as an overall group
makes studying the effects of different treatment
options challenging. MSAs provide a useful means
to substratify patients and there is already emerging
evidence of a differential response to treatment
between MSA subgroups. For example, in posthoc
subgroup analyses of the rituximab in myositis
study, a differential response to B-cell depletion
was seen, with antisynthetase and anti-Mi2 anti-
bodies being strongly predictive of improvement
with rituximab [40].
CONCLUSION
MSAs are clinically useful for facilitating diagnosis
and predicting prognosis in both adult and juvenile-
onset dermatomyositis and provide a unique oppor-
tunity to adopt a stratified approach to investigation
and management. We anticipate that the future
validation of alternative testing methods will permit
more widespread testing for MSA, enabling the diag-
nosis of dermatomyositis to be established without
the need for invasive tests such as muscle biopsy in
the majority of cases. Furthermore, MSA may in the
future prove to be useful in monitoring disease
activity and the response to treatment.
Acknowledgements
None.
Conflicts of interest
The authors declare no conflict of interest. The work of
Z.B. is part-funded by Association FrancaiseContre Les
Myopathies (AFM). S.T. is supported by the BMA Doris
Hillier grant 2012.
Volume 25
Number 6
November 2013

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